tbuckley/cabot-search huggingface dataset:
Abstract 3748: Epstein-Barr virus BART lncRNAs induce <i>IKZF3</i>/Aiolos to maintain EBV latency and promote tumorigenicity in nasopharyngeal carcinoma
Authors: Songtao He, Jiayan Liu, Bobo Wing-Yee Mok, Sai Wah Tsao, Honglin Chen
Journal: Cancer Research (2023)

Abstract Epstein-Barr virus (EBV) maintains latency in its associated tumors, including nasopharyngeal carcinoma (NPC), expressing very few viral proteins but abundant levels of noncoding RNAs (mainly EBERs and BARTs) in NPC cells. We found that IKZF3/Aiolos is a downstream target of BART lncRNAs in NPC cells. The functions of BART lncRNAs and IKZF3 in EBV latency and pathogenesis of NPC remain elusive. In this study, meta-analysis of eight EBV-associated studies showed that IKZF3/Aiolos was consistently upregulated in EBV-infected NPC cells. Our study further showed that transcription of IKZF3/Aiolos is highly upregulated in EBV-infected NPC cells and clinical tissue samples due to the action of EBV encoded BART lncRNAs, with IKZF3/Aiolos was expressed at higher levels in late stage (stage III &amp; IV) NPC patients than in early stage (stage I &amp; II) disease. Secondly, we found that IKZF3/Aiolos was upregulated in BART-activated NPC cells but downregulated in BART-knockdown NPC cells. In addition, this study further demonstrated that IKZF3/Aiolos modulates transcription of EBV BZLF1 and the cellular gene, LRIG1, to maintain EBV latency and promote NPC tumorigenesis in vitro and in vivo. Our results showed that the EBV lytic reactivator BZLF1 was upregulated in IKZF3/Aiolos knockout or Aiolos inhibitor-treated NPC cells. ChIP-qPCR, immunoprecipitation and immunofluorescence analyses further revealed that IKZF3/Aiolos induces H3K27 deacetylation to silence expression of BZLF1 and maintain EBV latency in NPC cells. Moreover, functional analyses and western blotting showed that IKZF3/Aiolos inhibited the tumor suppressor, LRIG1, to upregulate expression and phosphorylation of the cellular proto-oncogene Erb-B2 for NPC pathogenesis. Sphere- and colony-formation assays demonstrated that IKZF3/Aiolos enhances growth of NPC cells in vitro, and in vivo experiments further showed that IKZF3/Aiolos promotes tumorigenicity of NPC cells in NOD mice. Mechanically, we found that the expression of EBV lytic reactivator BZLF1 and cellular LRIG1 were negatively regulated by BART lncRNA/IKZF3/Aiolos regulatory machinery in NPC cells, while Erb-B2 was positively regulated, which indicated that IKZF3/Aiolos is a new biomarker for NPC and may lead to the development of novel diagnostic tests and treatments for NPC. Citation Format: Songtao He, Jiayan Liu, Bobo Wing-Yee Mok, Sai Wah Tsao, Honglin Chen. Epstein-Barr virus BART lncRNAs induce IKZF3/Aiolos to maintain EBV latency and promote tumorigenicity in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3748.
Abstract 3735: N-terminal and C-terminal elephant-to-human p53 variants and truncations alter p53 transactivation
Authors: William H. Yang, Wei-Hsiung Yang
Journal: Cancer Research (2023)

Abstract Cancer is one of the most dreaded diseases of the 21st century for humans. Currently, the human cancer mortality rate is approximately 11-25%. However, for some animals, such as elephants, the cancer mortality rate is lower than 5%. p53 is a significant cellular regulator in human cancers, and its important role in response to DNA damage has been highlighted by the discovery of p53 retrogene found in elephants (19 copies) but not humans (0 copies). Therefore, the main question is whether (1) more copies of p53 are better at combating cancer development or (2) is elephant p53 is better than human p53 in p53-mediated function? Herein, we demonstrate for the first time that N-terminal and C-terminal elephant-to-human p53 variants and truncations alter p53 transactivation. First, we created elephant-to-human p53 variants (such as T387R, L383P, LSTEL, etc.) and truncations at the N-terminus and C-terminus of human p53. Secondly, R175H and R273H p53 mutants (conformational and contact mutants, respectively) were used as negative control. Using a p53 (14X) response element LUC and several natural p53 downstream gene promoters, we demonstrated that several N-terminal and C-terminal p53 variants and truncations increases p53 transactivation compared to WT p53. Moreover, we found that deletion of the region between aa374 and aa382 is integral for p53 transactivation. Taken together, our preliminary results demonstrate that several N-terminal and C-terminal elephant-to-human p53 variants enhance p53 transactivation and possible stability. This data is the first step to support the notion that elephant p53 is better than human p53 in p53-mediated function. Citation Format: William H. Yang, Wei-Hsiung Yang. N-terminal and C-terminal elephant-to-human p53 variants and truncations alter p53 transactivation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3735.
Abstract 49: Comparison of subcutaneous and orthotopic tumor growth in syngeneic mouse models of ovarian and renal cancer
Authors: Mari I. Suominen, Justyna Zdrojewska, Yvonne Konkol, Katja M. Fagerlund, Mervi Ristola, Jukka P. Rissanen
Journal: Cancer Research (2023)

Abstract Oncology drug development has markedly lower success rate (3.4%) than other indications (20.9%) as reported by Wong, Siah and Lo in 2019. Animal models are often pointed at as the culprits for failure in clinical trials. While better animal models for cancer are needed and constantly developed, the incentive of drug developers to use those might not be clear, because the regulatory authorities do not require it. Subcutaneous tumors have earned their place in drug development but adding more sophisticated models to the testing panel before entering the clinical phase should improve the success rate. We present here the properties of subcutaneous and orthotopic tumor growth in two syngeneic models. HM-1 murine ovarian cancer cells were inoculated subcutaneously (s.c.) and intraperitoneally (representing the stage of intraperitoneal carcinomatosis) and murine renal adenocarcinoma Renca cells s.c. and orthotopically within the renal capsule. Body weight and tumor growth were followed, and mice were sacrificed according to humane endpoint criteria. To compare tumor growth in s.c. sites and within the abdomen, the tumor weight at sacrifice was divided by the number of days since the inoculation. In the HM-1 model, the mice with intraperitoneal tumor were sacrificed due to build-up of ascites on average six days earlier that the mice with s.c. tumor. In s.c. HM-1 tumor-bearing mice, the reason for sacrifice was tumor ulceration. In the Renca model, the s.c. and intrabursal models were approximately the same length. There was a striking difference in the tumor growth rate (mg/day) in s.c. versus abdominal sites in both models. The growth was 4-5 times faster in the abdominal sites than subcutaneously, highlighting the effect of tumor specific microenvironment. It is easy to understand that having promising results might be easier in a slower growing model. However, since both ovarian and renal cancer show very different growth kinetics within the abdominal cavity, testing drug candidates aimed for those indications in orthotopic models before accessing the clinical trials could give a more relevant evaluation of the potency of the drug candidates. Citation Format: Mari I. Suominen, Justyna Zdrojewska, Yvonne Konkol, Katja M. Fagerlund, Mervi Ristola, Jukka P. Rissanen. Comparison of subcutaneous and orthotopic tumor growth in syngeneic mouse models of ovarian and renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 49.
Abstract 4911: A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer
Authors: Eunsun Jung, Seojin Jang, Daeil Sung, Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Yong koo Kang, So Ra Seock, Jung Min Park
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) harbors a higher cancer stem cell (CSC)-like population and exhibits a more aggressive metastatic phenotype. Due to the limitations of currently available targeted therapies, there remains a significant unmet need for the development of new targeted therapies for TNBC. Molecular chaperone heat shock protein 90 (HSP90) is attracting attention as an ideal therapeutic target due to it regulates essential biological functions such as cell proliferation, angiogenesis and metastasis. Although N-terminal HSP90 inhibitors have had little clinical success to date, C-terminal HSP90 inhibitors have received relatively little attention. We sought to investigate the effects of a new rationally designed NCT-547 on apoptosis, breast cancer stem cell (BCSC)-like properties, migration ability and heat shock response (HSR) in vitro and tumor growth and metastasis in CSC-enriched allograft model in vivo. NCT-547 inhibits TNBC cell proliferation by simultaneously inactivating several survival factors including AKT, MEK, and STAT3. In addition, NCT-547 effectively targets BCSC-like properties with impairment of ALDH1 activity, CD44+/CD24- phenotype, and 3D mammosphere-forming ability. The expression of HSF-1 target genes such as Hsp90, Hsp70, Hsp27, Hsp40 and Hsp65 is highly overexpressed in TNBC patients. The mRNA abundances of target genes were significantly decreased after NCT-547 challenge. NCT-547 effectively targets both the proliferating TNBC tumor cells and CSCs, markedly reducing tumor growth, coinciding with decreased Ki-67 proliferation index and enhanced apoptosis. Anti-tumor effect of NCT-457 was independent of heat shock response as evidenced by significant downregulation of HSF1 phosphorylation and expression of downstream targets HSPs members. It is noteworthy that NCT-547 did not affect markers of hepatic and renal acute toxicity and was not cytotoxic in non-malignant cells. NCT-547 may therefore have potential to address current limitations in the treatment of TNBC. Citation Format: Eunsun Jung, Seojin Jang, Daeil Sung, Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Yong koo Kang, So Ra Seock, Jung Min Park. A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4911.
Abstract 3826: Potency of cardiac glycosides by structure in organotypic models of pancreatic and ampullary carcinomas
Authors: Md Shahadat Hossan, Ethan Lin, Austin Stram, Jamie Warner, Luke Koeppel, Ellie Riedl, Jeremy Kratz
Journal: Cancer Research (2023)

Abstract Background: Organotypic models have emerged as an important preclinical model for developmental therapeutics in pancreatic and biliary cancer. Naturally derived cardiac glycoside in 2D monoculture exquisite potency, here we describe their activity in cancer and normal liver with patient-derived cancer organoids (PCOs). Methods: PCOs of pancreatic and ampullary cancers and normal hepatic tissues were generated. Response was assayed with four structurally different cardiac glycoside (cerberin, neriifolin, digitoxin, digoxin; 72h). Response was characterized by growth inhibition (GI50) using 3D CellTiterGlo (CTG) and subclonal population response by high content imaging using normalized change in diameter (n=1038). Results: Dose response revealed improved potency for cerberin and neriifolin, versus digoxin and digitoxin across models (see table). In a normal liver organoid model, there was no convergence in dose response observed when extended to 1uM of each cardiac glycoside. Ampullary PCO response was assayed using subclonal population analysis. Cerberin at 10nM achieved growth arrest across the population as assayed by median Δ diameter (growth +4.0±32.0, GΔ=0.94, p&amp;lt;0.005). Neriifolin at 10nM had subclonal with residual growth representing 72% of overall population as assayed by Δ diameter (growth +18.3%, GΔ=0.65). Traditional cardiac glycosides of digoxin and digitoxin at 10nM had significant portions with residual growth (94.9% and 84.7%, respectively) as well as did not achieve meaningful effect (GΔ=-0.10 and GΔ=0.05, respectively). Conclusions: CGs have varied potency for anticancer activity between different structural motifs. Cerberin induce population growth arrest in cancer models which differed from normal liver. This work requires dedicated mechanistic modeling to explain differences in anti-cancer activity that may confer sensitivity and in considering models of cardiac toxicity. Potency of Cardiac Glycosides in Organoid Models. GI50 (nM) Ampullary GI50 (nM) Pancreatic GI50 (nM) Normal Liver Cerberin 7.4 7.20 71.0 (NC) Neriifolin 10.2 7.4 62.0 (NC) Digoxin 29.6 47.9 55.5 (NC) Digitoxin NC 40.0 85.5 (NC) Citation Format: Md Shahadat Hossan, Ethan Lin, Austin Stram, Jamie Warner, Luke Koeppel, Ellie Riedl, Jeremy Kratz. Potency of cardiac glycosides by structure in organotypic models of pancreatic and ampullary carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3826.
Abstract 2805: Pharmacogenomic platform using patient-derived cells to delineate tumor heterogeneity and therapeutic response of refractory lung cancer
Authors: Charny Park, Sehwa Hong, Mihwa Hwang, Youngjoo Lee, Bo Ram Song, Eun Hye Kang, Hanna Sim, Beung-Chul Ahn, Kum Hui Hwang, Namhee Yu, Sunshin Kim, Ji-Youn Han
Journal: Cancer Research (2023)

Abstract A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for advanced or refractory lung cancer patients. Drug sensitivity screening was acquired from short-term PDC culture and multi-omics datasets were acquired from lung cancer PDCs (n = 199). Integrative analysis was performed to explore susceptible drug candidates from genetic variants, gene expression, and clinical profiles. To demonstrate PDC heterogeneity and its therapeutic response, cellular subpopulation was identified from single cell transcriptome from the patients (n = 8) harboring EGFR mutations with poor response to EGFR-TKIs. Mutation and gene expression profile of our PDC samples conserved with lung cancer tissue. Poor survival mutations were observed in KRAS, PDGFA, KEAP1, and MET. EGFR rare variants facilitated fast progression as well as poor susceptibility in EGFR-TKIs. PDC therapeutic subtypes classified patients into five groups: (1) epithelial-to-mesenchymal transition (EMT)-like (30.6 %), (2) EGFR-dominant (21.4 %), (3) stemness (19.4 %), (4) angiogenesis (17.3 %), and (5) inflammatory (11.2 %). The subtypes implicated in distinct pathway regulation activation, variant enrichment, pathologic type, and survival as well as therapeutic candidates. Meanwhile, single cell transcriptome uncovered IDO1 and MET activation of EGFR-TKI resistance cancer cells. Stromal cell clusters exhibited the variety according to combinatorial immunotherapy response. While VEGFA+, and TOP2A+ clusters exhibited well response to angiogenesis and DNA damage target drug combinations of patients, CALB2+ cluster was clearly abundant to non-responder patients. We could detect angiogenesis (dasatinib) and DNA damage (irinotecan) drug candidates according to stromal clusters’ scoring from bulk PDC samples. Our PDC platform recapitulated the molecular characteristics of solid lung tumor tissues including tumor microenvironment. Uncovered molecular mechanism implied drug candidates. Citation Format: Charny Park, Sehwa Hong, Mihwa Hwang, Youngjoo Lee, Bo Ram Song, Eun Hye Kang, Hanna Sim, Beung-Chul Ahn, Kum Hui Hwang, Namhee Yu, Sunshin Kim, Ji-Youn Han. Pharmacogenomic platform using patient-derived cells to delineate tumor heterogeneity and therapeutic response of refractory lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2805.
Abstract 6101: PUM3 is a novel R-loop regulator and is essential for efficient DNA damage repair
Authors: Chenyu Lin, Jian Ouyang, Robert Wine, Chen Qiu, Jason Williams, Traci M. Hall, Lee Zou, Wayne Miles
Journal: Cancer Research (2023)

Abstract R-loops have important roles in regulating transcription and genome integrity. To identify novel proteins that function to modulate DNA damage repair, we screened a library of CRISPR-engineered RNA binding protein knock-out cells. From this analysis, we found that a poorly characterized protein, PUM3, is important DNA damage repair and that PUM3-deficient cells were very sensitive the chemotoxic agents. We show that under normal conditions, PUM3 is localized to the nucleolus and nucleus, where it binds to R-loops and modulates transcription. In this setting, PUM3 functions to suppress/resolve R-loops and that PUM3-/- cells have elevated R-loop levels. Following DNA damage, PUM3 is rapidly re-localized from the nucleolus to sites of DNA damage in the nucleus by members of the DDX/DHX family of RNA-helicases. Using small molecule inhibitors and quantitative assays, we find that PUM3 functions in homologous recombination (HR) mediated DNA repair and that PUM3-/- cells have significantly reduced HR-efficiency. PUM3 function at sites of DNA breaks are not affected by transcription or R-loops, implicating PUM3 as functioning after DNA resection during DNA repair. Analysis of TCGA patient data shows that PUM3 levels correlate with Cisplatin resistance and patient outcome. Collectively, our data shows that PUM3 is a previously unknown regulator of R-loops and DNA damage repair that has an important role in chemotherapy sensitivity in cancer patients. Citation Format: Chenyu Lin, Jian Ouyang, Robert Wine, Chen Qiu, Jason Williams, Traci M. Hall, Lee Zou, Wayne Miles. PUM3 is a novel R-loop regulator and is essential for efficient DNA damage repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6101.
Abstract 3079: Characterization of ER-AF2 inhibitors in breast cancer
Authors: Jane Foo, Francesco Gentile, Joseph Lee, Helene Morin, Shabnam Massah, Maria Guo, Jason Smith, Fuqiang Ban, Artem Cherkasov, Nada Lallous
Journal: Cancer Research (2023)

Abstract Up to 80% of breast cancers (BCa) rely on the estrogen receptor (ER) for their growth and progression. This dependence on ER has led to many hormonal therapies that target this receptor. However, almost 40% of these cancers will acquire resistance over the course of the treatment period. One potential cause of resistance is mutations in the estrogen binding site (EBS) of ER. As such, there is an increasing need for novel inhibitors that targets ER at a site separate from the EBS. Here, we propose targeting the activation-function (AF2) pocket of ER that is important for cofactor binding and transcription activation. Billions of compounds were screened through an in-silico deep docking method, and potential AF2 inhibitors were then validated in cell-based and biophysical assays. We tested the effect of potential AF2 inhibitors on ER transcriptional activity using luciferase reporter assay in ER-positive T47D-kbluc cells. We then evaluated the effect of molecules on cell viability of ER-positive T47D and ER-negative MDA-MB-231 cells using PrestoBlue assays in order to exclude off-target effects. From these cell-based assays, we identified several inhibitors that effectively reduced transcriptional activity and viability in ER-positive T47D cells at low micromolar concentrations. We conducted PGC-1α peptide displacement assay to confirm their AF2 binding and estradiol displacement assays to exclude any binding to the EBS. Proximity ligation assay (PLA) showed disruption of the interaction between ER and coactivator SRC-3 upon treatment with ER-AF2 inhibitors in T47D cells. Current work focuses on confirming the direct binding between the compounds and recombinant ER-ligand binding domain by various biophysical assays (MST, BLI, and ITC). Future work aims to solve the structure of ER-LBD in a complex with our lead compound by X-ray crystallography. We predict that the use of potent ER-AF2 inhibitors along with current treatments, will provide a novel tactic that can act as a complementary therapeutic to target treatment resistance in ER+ BCa. Citation Format: Jane Foo, Francesco Gentile, Joseph Lee, Helene Morin, Shabnam Massah, Maria Guo, Jason Smith, Fuqiang Ban, Artem Cherkasov, Nada Lallous. Characterization of ER-AF2 inhibitors in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3079.